Tramadol hydrochloride, (1RS, 2RS)-2-(dimethyl-amino)-methyl-1-(3-methoxyphenyl)-cyclohexanol HCl (tramadol), is a centrally-acting analgesic that has an unexpected distinction from morphine, the prototype pure opioid analgesic. Although tramadol was introduced into clinical practice in the 1970s without expectation of mechanistic differences from opiates, the data gathered to date in preclinical studies, clinical trials, epidemiological reports, and widespread use in patients indicate that a differentiation is appropriate. Tramadol is an atypical centrally acting analgesic in that its efficacy appears to be attributable to multiple mechanisms of action. The compound and its enantiomers bind with weak affinity to rodent and human μ-opioid receptors and with less affinity for δ- or κ-Opioid receptors. Tramadol's O-desmethyl metabolite binds with higher affinity than the parent compound, but still with much lower affinity than morphine. Thus, activation of μ-opioid receptors appears to be one of the components of tramadol's mechanism of action, but insufficient on its own to explain tramadol's antinociceptive and analgesic potency and efficacy.
A second, non-opioid component is suggested by several observations that include the incomplete naloxone reversibility in most animal models and in human trials; and, the attenuation of its antinociceptive or analgesic effect by non-opioid antagonists. Hence, the results are consistent with dual contributions, opioid and non-opioid, with the predominant contribution perhaps being dependent upon the species, route of administration, or particular nature of the pain. The source of the dual mechanisms has been hypothesized to arise from the different pharmacologies of the two enantiomers of tramadol, one being more opioid-like than the other.
Analgesics that operate via the μ-opioid receptor are typically phenols and phenol ethers. They frequently suffer from the drawback that they are metabolically inactivated by conversion to glucuronides, which are rapidly excreted. The carboxamide group has been found to be an effective bioisosteric surrogate for the phenol group in certain benzomorphans and morphinans, which has led to a series of opioids with a superior biological lifetime (Wentland, M. P. et al. Bioorg. Med. Chem. Lett. 2001, 11(5), 623-6; Wentland, M. P. et al. Bioorg. Med. Chem. Lett. 2001, 11(13), 1717-1721; Bidlack, Jean M. et al. J. Pharmacol. Exp. Ther., 2002, 302(1), 374-380).
The preparation of certain 1-aryl-(2-dialkylaminomethyl)cycloclohexan-1-ols is disclosed in PCT application WO 03/080557 (CA2480038), issued Oct. 10, 2003 (Sundermann, B. et al, Grünenthal GMBH Assignee.). A genus of tramadol analogs is disclosed in PCT application WO 03/048113, issued Jun. 12, 2003 (Senanayake, C. H. et al., Seprecor Assignee).
Thus there is a need to address the metabolic inactivation of tramadol that occurs through the conversion of its hydroxy metabolite to the corresponding glucuronide. The present invention replaces the methoxy substituent of tramadol with a carboxamido group.